Background: Thyroid cancer: The incidence of thyroid cancer has doubled over the last two decades. Although most patients with thyroid cancer of follicular cell origin have an excellent prognosis, 10% - 15% will have refractory disease to conventional therapy (resection combined with radioiodine ablation and thyroid hormone for TSH suppression). Chemotherapy and external beam radiation are ineffective in patients with metastatic disease. The overall 10 year survival of patients with metastatic thyroid cancer of follicular cell origin is approximately 40-50%. Anaplastic thyroid cancer is one of the most lethal solid malignancies with no currently available effective systemic therapy. Adrenocortical carcinoma: Approximately two-thirds of patients who present with adrenocortical carcinoma have locoregional disease and metastasis. Unfortunately, despite combined multimodality therapy, the overall prognosis of patients with adrenocortical carcinoma remains dismal, with a 5-year survival of less than 35%. Summary: We have made progress towards identifying molecular targets and novel agents for thyroid and adrenocortical carcinoma therapy. From our pangenomic studies of endocrine cancers (thyroid and adrenal), we have identified altered genes/pathways which are druggable targets such as dysregulated methylation of tumor suppressor genes and histone deacetylase expression, and elevated survivin expression in poorly differentiated and anaplastic thyroid cancer. By integrating this data with our quantitative high throughput drug library screening of over 3,000 compounds, which demonstrated enriched activity of compounds targeting dysregulated genes/pathways in thyroid cancer cells. We have completed preclinical studies of 5 agents which showed excellent activity inhibiting growth and metastases of thyroid cancer cells (4 agents) and adrenocortical carcinoma cells (1 agent). Moreover, we have identified biomarkers of response to treatment validated in our preclinical studies that are present human thyroid and adrenocortical carcinoma tissue samples. We have completed combination compound matrix drug screening of 28 active compounds and have identified 4 synergistic agents which we are evaluating in our preclinical models.